Background:
The dose of inhaled medication reaching a patient is dependent on drug formulation,
method of delivery, output and correct use of the delivery device and frequency of use.
The most commonly used aerosol drug delivery device in preschool children is the
pressurised metered-dose inhaler (pMDI) -spacer. This study evaluated strategies for
improving the delivery of inhalation therapy in preschool children by focusing on factors
affecting the optimal use of pMDI-spacers and on the frequency of their use as determined
by adherence to prescribed drug regimes.
The study was divided into two parts. Part 1 examined the number and type of breaths
needed for efficient drug delivery through a pMDI-spacer in preschool children. Part 2 was
a randomised, controlled, prospective clinical trial in which a comparison was made
between an incentive spacer device and a small volume spacer with respect to adherence,
correct device use (spacer technique) and clinical outcome.
Overall aims:
⢠To determine how many tidal breaths are required to effectively inhale medication
from different types of spacer/ valved holding chamber devices, and to determine the
efficacy of a single maximal inhalation for drug delivery in young children.
⢠To investigate the relationship between factors that determine dose delivery of
inhaled asthma maintenance therapy and symptom control in preschool asthmatic children.
⢠To determine the influence of an incentive inhalation delivery device on drug
delivery and clinical outcome in preschool asthmatic children. Part One (Chapters Two and Three):
Background: The pMDI-spacer combination is currently the most commonly used method
of drug delivery to preschool asthmatics. A patientâs competence in using a pMDI-spacer
is an important part of drug delivery. Preschool children are instructed to breathe normally
(tidally) through spacer devices. There is little evidence on the number of breaths required
for optimal drug delivery. Whether the single maximal breath technique has a place in
spacer use in preschool children also remains unclear. Due to a lack of data, authors of
asthma guidelines have been unable to give evidence-based instruction on how a preschool
child should breathe through a spacer.
Aims: To determine the optimal method of breathing through a spacer for preschool
asthmatic children to ensure effective drug delivery.
Hypothesis: Based on technical data on in vitro spacer performance and knowledge of tidal
flow patterns in young children the hypothesis is that a limited number of breaths would be
sufficient for efficient drug inhalation via spacer in preschool children.
Methods: A method for reliably recording and simulating breathing of patients using
pMDI-spacer devices was designed, constructed and validated. Breathing flow patterns
were recorded in preschool children inhaling placebo from spacers. The breathing patterns
were reproduced by a breathing simulator which was connected to spacer devices.
Breathing patterns previously recorded using each specific type of spacer, were simulated
with the corresponding spacer type. To estimate delivery, the mass of salbutamol was
measured on a filter interposed between the spacer and the simulator. Four different spacer
devices, the Aerochamber Plus®, Funhaler®, Volumatic® and a modified 500ml plastic
soft drink bottle were tested with a salbutamol pMDI. The effect of different numbers of
tidal breaths and that of a single maximal breath on drug delivery were compared.
Results: Drug delivery via the Funhaler® mean (95CI) was 39% (34-43) and 38% (35-42)
of total dose recovered from filter, pMDI and spacer, for two and nine tidal breaths
respectively. Drug delivery via the Aerochamber Plus mean (95CI) was 40% (34-46) and
41% (36-47) for two and nine tidal breaths respectively. There was no significant difference in drug delivery after three tidal breaths mean (95CI) 40% (36-44%) and nine
tidal breaths nine tidal breaths; mean (95CI) 37% (33-41) for the Volumatic®. With the
(unvalved) modified soft drink bottle, there was no significant difference in drug delivery
between two, five or nine tidal breaths.
Inhalation volumes were almost double the expected tidal volumes. The inhalation volume
means (SD) of subjects using the Aerochamber Plus®, the Funhaler®, the Volumatic® and
the modified soft drink bottle were respectively 393ml (247), 432ml (225), 384ml (185),
445ml (167) during tidal breathing and 515ml (164), 550ml (239), 503ml (213), 448ml
(259) for the single maximal breath manoeuvre.
100% of seven year old children, 84% of six year olds, 76% of five year olds, 38% of four
year olds and 20% of three year olds could perform a single maximal breath manoeuvre.
Nine tidal breaths resulted in significantly greater drug delivery to filter than single
maximal inhalation for both the Funhaler® (p=0.04) and the Volumatic® (p=0.01). There
was no significant difference in drug delivery to filter between single maximal inhalation
and nine tidal breaths with both the Aerochamber Plus® and the modified soft drink bottle.
Conclusion: In preschool children, two tidal breaths were adequate for drug delivery
through small volume valved spacers and a 500ml modified soft drink bottle. For a large
volume spacer, three tidal breaths were adequate for drug delivery.
Part Two (Chapters Four and Five):
Background: Drug delivery by pMDI-spacer is determined by many different factors,
including spacer technique and adherence to prescribed medication. The effect of both
spacer technique and adherence on clinical outcome has been demonstrated in older
asthmatics. In this part of the thesis the influence of these factors on clinical outcome in
preschool asthmatics was firstly investigated. Thereafter, the additional influence of an
incentive spacer device on adherence, spacer technique and clinical outcome was also
assessed.
Aims:
⢠To investigate the effect of proficiency in spacer technique, as measured by
deposition of drug inhaled onto a filter, on clinical outcome in preschool asthmatic
children.
⢠To investigate the effect of adherence to prescribed inhaled asthma medication on
clinical outcome in preschool asthmatic children.
⢠To investigate the influence of the use of an incentive spacer device on inhaled drug
dose, adherence to prescribed treatment and clinical outcome in preschool asthmatic
children.
Hypothesis:
⢠Proficiency in spacer technique correlates positively with improved clinical
outcome.
⢠Good adherence to prescribed medication regimens correlates positively with
improved clinical outcome.
⢠Use of an incentive spacer device, the Funhaler® , improves both competency in
spacer technique and adherence to prescribed medication and thereby improves clinical
outcome in preschool children with asthma. Methods: A prospective randomised, controlled clinical trial was performed. Subjects
were two to six year old children who had doctor-diagnosed asthma and were on daily
maintenance therapy with inhaled corticosteroids. Maintenance therapy was delivered by
Funhaler® in the study group and Aerochamber Plus® in the control group. Subjects were
assessed for the following outcomes at three-monthly intervals for one year:
(1) Proficiency in spacer technique was measured at each study visit by measuring the
drug dose deposited on a filter interposed between the subject and the spacer.
(2) Adherence was monitored using an electronic monitoring device (Smartinhaler)
(3) Asthma symptoms were monitored using diary cards.
(4) Quality of life (QoL) was measured using the PedsQL questionnaires.
(5) Lung function was monitored using the forced oscillation technique.
The Funhaler group was then compared with the Aerochamber Plus group in terms of
determinants of drug delivery and markers of clinical outcome.
Results: One hundred and thirty two subjects were included in the study. One hundred and
eleven patients (84%) completed the study. By the six month follow-up, significantly more
subjects in the Funhaler group had dropped out of the study (p=0.04).
Throughout the clinical trial, there was large intra-subject variation in proficiency in spacer
technique, as measured by drug dose deposited on filter. Individual patient drug doses
recovered from the filters ranged from zero to 136μg (calculated as the mean of five 100μg
pMDI actuations). There was no significant correlation between proficiency in using the
delivery device and any measure of asthma control (p > 0.05). Correcting for age, gender,
and adherence to prescribed medication did not influence the results.
Inter subject variability in adherence to prescribed medication was extremely high
throughout the study. Adherence to prescribed medication ranged from 1% to 99%. There
was a significant correlation between adherence to prescribed medication and nights
without wheeze, throughout the study period (r = 0.01; p = 0.01). The correlation between
adherence to prescribed medication and nights without wheeze remained after correcting
for age, gender, proficiency in spacer technique, and the number of nights without wheeze
at the baseline visit (r = 0.01; p = <.01). There was also a significant correlation between
adherence to prescribed treatment and (daytime) days without wheeze (r = 0.01; p = 0.01).
The correlation ceased to be significant after correcting for age, gender, proficiency in spacer technique, and (daytime) days without wheeze at the time of the baseline visit.
There was a significant correlation between adherence to prescribed medication and
bronchodilator free days (r = 0.01; p = 0.02) throughout the study. After correcting for age,
gender, proficiency in spacer technique, and bronchodilator free days at baseline, the
correlation between adherence to prescribed medication and bronchodilator free days
remained significant (r = 0.01; p = 0.01). There was no significant correlation between
adherence and other markers of clinical outcome.
After correcting for age and gender, the Funhaler group demonstrated significantly higher
proficiency in spacer technique as determined by filter dose (p = 0.05). The improved
proficiency in spacer technique in the Funhaler group was limited to subjects who were
younger than 4 years of age at the baseline visit (p < 0.01).
There was no significant difference in adherence to prescribed medication between the
Funhaler group and the Aerochamber Plus group (p = 0.93). Correcting for age and gender
did not influence the results.
At the start of the clinical trial (baseline visit), the Funhaler group reported significantly
less days without wheeze (p = 0.03), and significantly less bronchodilator free days (p =
0.02) than the Aerochamber Plus group in the seven days before the baseline visit. The
Funhaler group also scored lower than the Aerochamber group in terms of QoL scores at
the time of randomisation (p = 0.05). Where needed, various measures were used to correct
for the significant differences at baseline, between the Funhaler group and the
Aerochamber Plus group. There was no significant difference between the Funhaler group
and the Aerochamber Plus group in terms any of clinical outcome measures used.
Correcting for age, gender did not influence the results.
Discussion: Use of the Funhaler® therefore appeared to specifically improve drug delivery
in those subjects who, with a conventional spacer, would have inhaled very low doses of
medication. The Funhaler® was therefore partially successful as an incentive device, as its
use positively influenced drug delivery in a specific sub-group of preschool children.
Proficiency in spacer technique did not translate to improved clinical outcomes. Various
reasons for the lack of association between proficiency in spacer technique and clinical outcome, including the inevitable inherent limitations in design in a clinical study, are
discussed.
Results suggest that adherence to prescribed medication regimens correlates positively with
improved clinical outcome in preschool children with asthma. Use of the Funhaler® did
not improve adherence to prescribed medication, or clinical outcome, in preschool children
with asthma. Funhaler® therefore failed as an incentive device to improve long term
adherence, and clinical outcome, in preschool asthmatic children. Future design for an
incentive device will need to consider providing feedback that is of more ongoing interest
to the child.
As the large variation, as observed in this study, in proficiency in spacer technique, and
adherence to prescribed medication, is likely to influence results of clinical trials, an
awareness of the variation in spacer technique and drug delivery may contribute towards
the accurate interpretation of results in future studies.
Finally, the wide variation in both proficiency in spacer technique, and adherence to
prescribed medication, both factors that determine drug delivery to patients, highlight the
importance of pursuing ways to improve inhalation drug delivery to preschool children in
order to eliminate the variability in prescribed medication that eventually reaches patients.
The delivery to the lungs of a constant, reliably repeatable inhaled drug dose should be a
continuing aim for aerosol scientists and physicians.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:ufs/oai:etd.uovs.ac.za:etd-12152010-123831 |
| Date | 15 December 2010 |
| Creators | Schultz, André |
| Contributors | Prof A Venter |
| Publisher | University of the Free State |
| Source Sets | South African National ETD Portal |
| Language | en-uk |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.uovs.ac.za//theses/available/etd-12152010-123831/restricted/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University Free State or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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